The clinical and commercial triumph of Wegovy® and Ozembic® has sparked a profound shift in drug discovery, repositioning peptides from niche signaling molecules to a frontline therapeutic modality. Researchers are leveraging peptides as therapeutic alternatives to small molecules in proximity modalities such as molecular glues. Further, delivery strategies can be facilitated by peptides to direct uptake of nucleic acids into cells. A second delivery strategy is in radiopharmaceutical applications, where high-affinity radiolabeled peptides offer specificity to a target and are rapidly cleared by the kidney to reduce toxicity. As showcased at the SLAS 2026 International Conference in Boston last week, peptide therapeutics are evolving from linear structures towards more complex architectures that offer new avenues for challenging targets. Peptides were also showcased for use as assay tools for drug discovery. The breadth of diversity in structure and sequence of peptides can create a discovery challenge, thus supporting the need for innovation in screening and validation assays.
Overcoming the Discovery Bottleneck
Traditional peptide synthesis strategies, including split-pool combinatorial approaches are powerful to generate thousands of peptides, yet lag behind display technologies that can generate billions of sequences. For example, phage display offers the ability to screen several billion molecules in a single tube in 3 days and offers selection environments to identify high-affinity binders in complex biological matrices. Alternatively, mRNA display offers opportunities to incorporate non-natural amino acids for enhanced stability and lead optimization. Deciding which to pursue depends on the target and distinct discovery goals. A key benefit to display technologies is the ability to screen dozens of libraries, in parallel that feature certain structural motifs. These motifs include linear and cyclic structures, fixed amino acid positions, and custom amino acid randomization schemes to cast a wide net for hit discovery while being conscience of time and consumption of critical reagents. Finally, incorporating sensitive detection technologies such as next generation sequencing (NGS) during analysis allows researchers to dive deeper into the data to find potential weak binders that offer starting points for optimization. These NGS datasets can feed into artificial intelligence / machine learning (AI/ML) models to guide hit-to-lead phases, discussed next.
Validation at Scale: From Hits to Leads
Once peptides have been discovered, they must to be validated in orthogonal binding assays. Many peptide drug discovery researchers continue to use traditional methodologies such as competition displacement assays, surface plasmon resonance (SPR) and bio-layer interferometry (BLI). Innovation in hardware and analysis has enabled testing over 20,000 interactions per day. Alternatively, workflows are now integrating affinity selection mass spectrometry (ASMS) in peptide discovery and validation workflows. ASMS offers the ability to directly measure the mass of peptides, generating higher confidence that the resulting binder matches the expected sequence. The ability to validate hits rapidly can feed into the design-make-test-analyze cycle, potentially including computational tools, to progress the most promising leads forward with confidence. Applying the right validation methodologies can achieve critical path and short timelines for lead optimization.
Operating at the Forefront of the Peptide Renaissance
Peptides are not just playing the role of initial drug lead, but the primary tool for unlocking the next generation of therapeutic targets. There are several factors to consider when initiating a peptide discovery campaign:
- Peptide Discovery Technology: Leveraging phage display and mRNA expertise to identify high-affinity binders for challenging targets can streamline discovery of early peptide hits faster than traditional synthesis approaches.
- Library Size: Jump start discovery using large peptide libraries of 1-10 billion different sequences in a single pass. The larger the library size the higher likelihood of success at discovering meaningful binders to the target of interest.
- High-Throughput Discovery and Maturation: Workflows that integrate both initial discovery, affinity maturation, and selectivity testing to optimize and validate hits can shorten lead generation timelines.
- Biophysical Characterization: Validation of binding starts with measuring the affinity and selectivity of binders to ensure quality and on-target activity to meet affinity milestones.
Whether you are looking to validate molecular glue mechanisms or accelerate peptide-based TPD programs, technical expertise and high-throughput capabilities are required to navigate these complex workflows. Overall, the goal is to ensure your discovery pipeline benefits from the same principles showcased at SLAS 2026: speed, precision, and scalability.
